The overall objective of this SBIR application is to develop a potent, selective and orally active GABA-A ?5 Positive Allosteric Modulator (PAM) for the treatment of Mild Cognitive Impairment due to Alzheimer?s Disease (MCI due to AD). There are currently no approved therapeutics for this indication making this an area of extremely high unmet need. There is strong support from preclinical AD models and human patients, particularly in this early stage of AD, that neuronal circuits in the hippocampus become excessively active contributing to neuronal pathology and brain dysfunction. AgeneBio?s GABA-A ?5 PAM program represents a novel approach to addressing the excess hippocampal activity in this patient population at high risk for dementia. The concept that reduction of hippocampal overactivity is therapeutically beneficial is supported by recent preclinical and clinical studies using the atypical antiepileptic levetiracetam. Ranging from research on age-associated memory impairment in rodents to clinical studies in patients with amnestic MCI, beneficial effects on key circuits in the medial temporal lobe/hippocampus and on memory performance have been demonstrated by treatment at low doses of levetiracetam that reduce hippocampal overactivity. The strong hippocampal localization of GABA-A ?5 receptors coupled with its role to control tonic inhibition make GABA-A ?5 PAMs well suited to reduce the excess hippocampal activity in MCI due to AD. Preclinical studies in rats with age-associated memory loss which show hippocampal overactivity demonstrate that selective GABA-A ?5 receptor PAMs are effective therapeutic agents to improve memory. The screening tree is well defined, all assays are in place, and compounds have advanced through the screening tree. The program lead series (funded by the Blueprint Neurotherapeutics Network) has potent and selective GABA-A ?5 PAM compounds with good in vivo efficacy in an age-impaired rat. However, should the lead series falter at any point for reasons independent of mechanism of action, it is critical that a second series be identified that could rapidly be evaluated to mitigate the overall program risk. The purpose of this SBIR grant is to expand the structurally distinct, non-BZD second series scaffold to identify potent and selective GABA-A ?5 compounds for the treatment of MCI due to AD.